文章：

化学耐药相关ABC转运体的结构、机制和靶向研究进展

Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters

原文发布日期：2023-09-15

DOI: 10.1038/s41568-023-00612-3

类型: Review Article

开放获取: 否

英文摘要：

Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR–Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer.

摘要翻译： 

癌细胞常常对化学结构多样的抗癌药物表现出固有或获得性耐药性，从而限制了治疗成功。这种多药耐药性的主要机制之一是介导药物外排的ATP结合盒（ABC）转运蛋白的过度表达，特别是ABCB1、ABCG2和ABCC1已被证实会导致癌症化疗耐药。高分辨率结构、生物物理学及计算机模拟研究极大促进了我们对这些ABC转运蛋白药物转运机制的理解，并且已有多种前景广阔的治疗方法被用于克服ABC转运蛋白介导的癌症化疗耐药，包括基于辐射的免疫疗法、热疗法以及纳米医学。本综述重点阐述了过去五年中在具有临床重要性的三种转运蛋白（ABCB1、ABCG2和ABCC1）方面取得的进展。我们基于结构信息探讨了其广谱底物特异性的分子基础，并讨论了阻断ABC转运蛋白功能的新策略。此外，简要探讨了通过CRISPR–Cas9对ABC转运蛋白进行基因修饰，以及重新设计氨基酸序列以将转运方向从外排转变为内输的方法。我们建议应利用当前关于ABC转运蛋白结构、功能及调控机制的信息开展临床试验，以提高癌症患者化疗药物的疗效。

原文链接：

Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters